Collagen I, the most abundant structural protein of connective tissue such as skin, bone and tendon, is first synthesized as a precursor molecule, procollagen. Formation of collagen fibrils is initiated by enzymatic processing of procollagen to expose telopeptides, which engage in site-specific intermolecular interactions to drive collage self assembly. In vivo, collagen fibrils are stabilized by the covalent cross-links formed between fibril-incorporated collagen molecules. Self assembly of collagen molecules results in collagen fibrils, the main component of fibrotic lesions, particularly scarring.
Collagen/collagen binding is mediated through the interaction of the C-terminal α1(I) and α2(I) telopeptides of one collagen molecule, and the Triple-helical Telopeptide-Binding Region (T-TBR) of another binding partner. The T-TBR is located within an α1(I) chain in the region flanked by resides 776 and 796 (Prockop, et al. (1998) J Biol Chem. 273, 15598-15604).
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. Types of fibrosis include, for example, pulmonary fibrosis (lungs), idiopathic pulmonary fibrosis (where the cause is unknown), cirrhosis (liver), endomyocardial fibrosis (heart), mediastinal fibrosis (soft tissue of the mediastinum), myelofibrosis (bone marrow), retroperitoneal fibrosis (soft tissue of the retroperitoneum), progressive massive fibrosis (lungs), nephrogenic systemic fibrosis (skin), Crohn's Disease intestine, keloid (skin), myocardial infarction (heart), scleroderma/systemic sclerosis (skin, lungs), arthrofibrosis (knee, shoulder, other joints) and some forms of adhesive capsulitis (shoulder).
Although the fibrotic changes seen in excessive scarring may be triggered in many ways, such as trauma, accidental injury or surgical procedures, most of them are developed through fundamentally similar pathways that, in the end, lead to altering a number of functions of involved tissues. For instance, after surgery in the abdomen, the formation of excessive scar tissue around abdominal organs often interferes with their functionality. After plastic surgery to the face, the formation of excessive scar tissue frequently compromises the benefits of the surgery. Excessive scar formation also presents a major complication in the eye after glaucoma surgery performed to maintain a lamellar channel from the subconjunctival space to the anterior chamber. Frequently, however, the excessive scar formation closes this pressure-reducing channel, thereby forcing the intraocular pressure to rise (Addicks, et al. (1983) Arch Ophthalmol. 101, 795-798). Yet another significant problem with excessive formation of fibrous deposits is the foreign body response to medical devices and materials implanted in the human body (Anderson, et al. (2008) Semin Immunol. 20, 86-100). Moreover, excessive scarring of the vocal folds may severely alter their ability to vibrate, thereby causing a number of voice disorders (Lim, et al. (2006) Ann Otol Rhinol Laryngol. 115, 921-929). Another medical problem of localized fibrosis is the formation of keloids, excessive scars for which there are no successful treatment methods. This particular scarring is an ongoing and rising problem; as keloids are more common in Americans of African and Asian descent, it is expected that in the near future the number of keloid cases in the USA will increase due to the foreseen rise in the percentage of these ethnic groups (Taylor, et al. (2002) J Am Acad Dermatol. 46, S41-62).
To date, no effective therapeutics for excessive fibrosis are available. What is needed are therapeutics and therapeutic methods that can prevent the excessive deposition of collagen fibrils that is characteristic of fibrotic processes, and to reduce localized and systemic fibrotic lesions.